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Targeted enhancement of flotillin-dependent endocytosis augments cellular uptake and impact of cytotoxic drugs

Farnaz Fekri, John Abousawan, Stephen Bautista, Roya M. Dayam, Costin N. Antonescu, Raffi Karshafian
doi: https://doi.org/10.1101/543355
Farnaz Fekri
1Department of Chemistry and Biology Ryerson University, Toronto Ontario, Canada, M5B 2K3
2Graduate Program in Molecular Science, Toronto Ontario, Canada, M5B 2K3
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John Abousawan
1Department of Chemistry and Biology Ryerson University, Toronto Ontario, Canada, M5B 2K3
2Graduate Program in Molecular Science, Toronto Ontario, Canada, M5B 2K3
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Stephen Bautista
1Department of Chemistry and Biology Ryerson University, Toronto Ontario, Canada, M5B 2K3
2Graduate Program in Molecular Science, Toronto Ontario, Canada, M5B 2K3
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Roya M. Dayam
1Department of Chemistry and Biology Ryerson University, Toronto Ontario, Canada, M5B 2K3
2Graduate Program in Molecular Science, Toronto Ontario, Canada, M5B 2K3
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Costin N. Antonescu
1Department of Chemistry and Biology Ryerson University, Toronto Ontario, Canada, M5B 2K3
2Graduate Program in Molecular Science, Toronto Ontario, Canada, M5B 2K3
5Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, Ontario, Canada
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  • For correspondence: cantonescu@ryerson.ca karshafian@ryerson.ca
Raffi Karshafian
2Graduate Program in Molecular Science, Toronto Ontario, Canada, M5B 2K3
3Department of Physics, Ryerson University, Toronto Ontario, Canada, M5B 2K3
4Institute for Biomedical Engineering, Science and Technology (iBEST), a partnership between Ryerson University and St. Michael’s Hospital, Toronto, Ontario, Canada
5Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, Ontario, Canada
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  • For correspondence: cantonescu@ryerson.ca karshafian@ryerson.ca
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ABSTRACT

Cellular uptake is limiting for the efficacy of many cytotoxic drugs used to treat cancer. Identifying endocytic mechanisms that can be modulated with targeted, clinically-relevant interventions is important to enhance the efficacy of various cancer drugs. We identify that flotillin-dependent endocytosis can be targeted and upregulated by ultrasound and microbubble (USMB) treatments to enhance uptake and efficacy of cancer drugs such as cisplatin. USMB involves targeted ultrasound following administration of encapsulated microbubbles, used clinically for enhanced ultrasound image contrast. USMB treatments robustly enhanced internalization of the molecular scaffold protein flotillin, as well as flotillin-dependent fluid-phase internalization, a phenomenon dependent on the protein palmitoyltransferase DHHC5 and the Src-family kinase Fyn. USMB treatment enhanced DNA damage and cell killing elicited by the cytotoxic agent cisplatin in a flotillin-dependent manner. Thus, flotillin-dependent endocytosis can be modulated by clinically-relevant USMB treatments to enhance drug uptake and efficacy, revealing an important new strategy for targeted drug delivery for cancer treatment.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted February 07, 2019.
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Targeted enhancement of flotillin-dependent endocytosis augments cellular uptake and impact of cytotoxic drugs
Farnaz Fekri, John Abousawan, Stephen Bautista, Roya M. Dayam, Costin N. Antonescu, Raffi Karshafian
bioRxiv 543355; doi: https://doi.org/10.1101/543355
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Targeted enhancement of flotillin-dependent endocytosis augments cellular uptake and impact of cytotoxic drugs
Farnaz Fekri, John Abousawan, Stephen Bautista, Roya M. Dayam, Costin N. Antonescu, Raffi Karshafian
bioRxiv 543355; doi: https://doi.org/10.1101/543355

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